Delta4, 5-3, 11-diketo-17, 20-dihydroxypregnanes and process



iatented May 23, 1956 UNITED STATES 17,20-DIHYDROXY- PREGNANES ANDPROCESS Lewis Hastings Sarett, to Merck & 00., Inc.,

" tion of New Jersey Princeton, N. 1., assignor Ral way, N. J a corporaiNo Drawing. Application July 13, 1946, Serial No. 683,428

This invention is concerned generally with novel chemical compounds ofthe cyclopentanod-imethylpolyhydrophenanthrene series and processes forpreparing the same; in particular it relates to stereoisomers of A",-3,11-diketo- 17,20-dihydroxy pregnene and acylated derivatives thereofand with methods of manufacturing these compounds from readily availablestarting materials. The newcompounds thus produced are of value in thepreparation of {hormones having androgenic activity such asadrenosterone and for other purposes. They are also of value as a meansof establishing the structure of other organic compounds.

These stereoisomeric A -3,11-diketo-1'7,20- dihydroxy pregnenes andtheir acylated derivatives, subject of this application, can berepresented by the following structural formula:

18 210E: OH: I ZOCHOR H: 5 0 FA AK 6 13 160B! H! i L14 L 1 m H- HIC2 l080H l i B L O: 3 4/5 6 7 Hz wherein R, is hydrogen or acyl. Thisformula, for purposes of convenience, is hereinafter reproduced below inthe abbreviated form:

I CHOR 9 Claims. (01 260-2973) re n right r the C17 carbon side chainthus: l V cm 7 in the latter case above the side chain thus CHOH-OH| (2)The stereochemical' relationship of rings A and B is indicated in theformulae by a solid line representing the valence bond in the cisconfiguration.

In accordance with the present invention, it is now found thatstereoisomers of A -3,11- diketo-17,20-dihydroxy pregnene and acylatedderivatives thereof, can be synthesized, and said M-3,11-diketo-17,20-dihydroxy pregnene converted to adrenosterone byreactions indicated generically as follows:

CH: HOR

HOB

O OH

I OH;

-HBr (2) Hy H l drolyr v I sis CHI CH: o CH;

oxidizing agent wherein R is acyl. The reactions indicated above areconducted as follows: The starting 7 material, a stereoisomer of4-bromo-3,11-diketo- -l7-hydroxy-20-acyloxy pregnene (1), which isprepared according to processes disclosed in my a co-pendingapplications, Serial No. 605,194, filed 601 July 14, 1944, nowabandoned; Serial No, 687,982,

filed August a 1946; s am No.683g12'7, filed my 13, 1946, now Patent No.2,493,780; and Serial No. 673,890 ifiled June 1, 1946, is reacted with Jof A -3,11-diketo-17,20-dihydroxy pregnene (3) which is reacted with anoxidizing agent to pro;

duce adrenosteronen (4). l r r In carrying out the reactions accordingto presently invented process, the ste'reois'omeric i Promo 3,11. 1dilseto rf -hy roxyJQ-acxbxv pregnane is: treated, for example byrefluxing. with a compound capable of removing the elements of hydrogenbromide, as for example, a tertiary amine such as pyridine, quinoline,picoline andthe like, causing the formation of the double bond in the4,5 position.

According to a preferred embodiment grapplicants process, the startingmaterial, 4r-bromo- 3,11 diketo 7 l7 (a) -hydroxy-20-acyloxy pregnane,is reacted directly, as for example by refluxing, with pyridine, toproduce the desired A -3,11-dil eto-17 (a) -hydroxy -20-acyloxypregavine t est u a rmu a: 7

wherein R is acyl. The last mentioned product can be: hydrolyzed by anyconvenient method, as

product can be represented by the following structural fo mula:

The product is recovered from the reaction mi tur in any con eni n W asr mp by d luting t esam wi h water a c in the adrenosterone product witha solvent such as chleroform, f om wh h t e ad ron i reqe ere in crud om by evaporat he c d produ t an be pur fied y o e io al ineth-' eds orample. by c ys l z n so vent s ch as et y alc q b o p ic for example, byreaction with aqueous alkaline methanolic solution, whereby A-i-3,11-diketo,-l7-(a)20-dihydroxy pregnene is obtained.

The productobtained at this stage is independent of the acyl group inthe starting material which can be any desired group derived for examplefrom acetic, propionic, butyric, valeric,

caprqic, capric, benzoic, or toluic acid, or; which the lower aliphaticacids, having 6 carbon atoms or less are preferred. a

' The, A '5;-3,1l-diketoJ'LZO-dihydroxy pregnene solvent. When thepreferred oxidizing agent,

periodic acid is employed suitable solvents inelude aqueous. methanol,aqueous, ethanol, aqueous dioxane, and the like; It is preferred tocon-J odic acid, under which conditions the time reuct obtained byoxidation is- A- 5.-3,11,1'7-*-triketoetiocholane known assadrenosterone. This duct, the reaction at abQut'20" C employing apeproximately threemolecular equivalents. of periabso ption. o su ma n VThe iollowing example illustrates a methodef carrying out the presentinvention, but it is to be understood that this example is given by wayof illustrat on and n (it limitation Ercmple About 700 mg. of4-bromo-3,ll-diketo-l'i-(a)- hydrox-y-ZO-aeetoxy pregnane; is dissolvedin about 20 cc. of dry pyridine and the solution heated to reflux forapproximately 8 hours. Thepyridine is evaporated under reduced pressure,the residual material is dissolved in chloroform and the chloroformextract. washed successively with dilute aqueous hydrQQhloric acid,aqueous sodium bicarbonate solution and finally with water. Thechloroform extract is, then evaporated to dryness under reduced:pressure and the residue purified by dissolving in. about 2 cc. benzene,adding about 30 cc. absolute ether and filtering off the flocculentprecipitate which ,forms, The filtrate is then evaporated to dryness,and the product recrystallized several times irom ether to producesubstantially pure Ae-sdlediketo-l'l-(a)-hydroxy-20-acetoxy-pregnene; M.P. 218-219" C. (corn). V H

ab ut 6. Q 4 -33. l?dij Y' droxy-20-acetoxy pregnene is dissolved inabout 5 cc. of methanol and a solution containing about 60 mg. ofpotassium bicarbonate, mg. of potassium carbonate and; about 2 cc. ofwater is added thereto. stand at about 20? C. for approximately 15hours, the solution is evaporatedito a small volume under reducedpressuraandis then extracted with chloreform. Thechloroforin extract iswashed with water and is then evaporated to dryness and the crudematerial thus obtained is purified by recrystallization from coldaqueous acetone to produce substantially pure 'A -3,11-diket0-17(a)!20-dihydroxy-pregnenehydrgate;M. P. 108 110 C.

(corn). V V

"About 85 mg. of; Afi atl-diketo-l'l -(M 20- d-ihydroxypregneneisdissolved-in about 2 of l 1 to stand at room temperaturetor-approximately 5 hours, water isaddedthere'to and the mixture is thenextracted withchloroform. The chloro- 1 formextract is-evaporated todryness and: the

residual material recrystallizedfrom: alcohol; to

produce substantial1y pure adrenosterone; M1: P.'

The resulting solution is allowed to .5 above can be purified bychromatographic absorption or sublimation prior to recrystallizationfrom alcohol.

Various changes and modifications may be made in my process as describedwithout departing from the scope of my invention. To the extent thatthese changes and modifications are within the purview of the annexedclaims, they are to be considered as part of my invention.

I claim:

1. The process of preparing adrenosterone which comprises reacting4-bromo-3,11-diketo- 17-hydroxy-20-acy1oxy pregn-ane with a tertiaryamine to remove the elements of hydrogen bromide from the molecule toform the corresponding A -3,11-diketo-17-hydroxy-2O-acyloxy pregnene;hydrolyzing this compound to the corresponding 17,20-dihydroxyderivative; and reacting the resulting A -3,l1-diketo-17,20-dihydroxypregnene with approximately three molecular equivalents of an oxidizingagent to produce adrenosterone.

2. The process of preparing adrenosterone which comprises reacting4-bromo-3,11-diketo- 17-(a)-hydroxy-20-acetoxy pregnene with Pyridine toremove the elements of hydrogen bromide from the molecule to form A-3,11-diketo- 1'7-(a)-hydroxy-20-acetoxy pregnene; reacting thiscompound with an alcoholic solution containing an alkali metal carbonateto effect saponiflcation of the ester grouping to produce A -3,11-diketo-l'fla),20-dihydroxy-pregnene; and reacting this compound withapproximately three molecular equivalents of periodic acid to produceadrenosterone.

3. The process which comprises reacting A 3,11-diketo-17,20-dihydroxypregnene with approximately thre molecular equivalents of an oxidizingagent to produce adrenosterone.

4. The process which comprises reacting A 3,11-diketo-1'7-(a)-20-dihydroxy pregnene with approximately three molecular equivalents ofperiodic acid to produce adrenosterone.

5. 20-substltuted-A -3Jl-diketo -17- hydroxypregnenes in which thesubstituent in the 20'- position is a radical selected from the classwhich consists of hydroxy and lower aliphatic carboxylic acyloxyradicals.

6. A -3,11-diket0-17-(a) -hydroxy -20- acetoxy pregnene, having amelting point of about 218- 219 C.

'7. A -3,11-diketo17-()-20-dihydroxy pregnene hydrate, having a meltingpoint of about IDS- C.

8. The process of preparing A -3,11-diketo- 17,20-dihydroxy-pregnenewhich comprises reacting4-bromc-3,1l-diketo-17-hydroXy-20-acyloXy-pregnane with a tertiary amineto remove the elements of hydrogen bromide from the molecule to form thecorresponding A -3,11-diketo- 17 -hydroxy-20-acyloxy-pregnene andhydrolyzing this compound to form said A -3,11-diketo-17,20-dihydroxy-pregnene.

9. The process of preparing A -3,11-diketo- 17((1),20-dihydroxy-pregnenewhich comprises reacting 4-bromo-3,11-diketo-1'7 (a) -hydroxy-20-acetoxy-pregnan with pyridine to remove the elements of hydrogen bromidefrom the molecule to form A -3,11-diketo-17(a)-hydroxy-20-acetoxy-pregnene and reacting this compound with analcoholic solution containing an alkali metal carbonate to effectsaponification of the ester grouping to produce said A-3,11-diketo-17(a), 20-dihydroxy-pregnene.

LEWIS HASTINGS SARETT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,153,700 Serini Apr. 11, 19392,239,742 Serini Apr. 29, 1941 2,254,562 Bockmuhl Sept. 2, 19412,389,325 Reichstein Nov. 20, 1945

1. THE PROCESS OF PREPARING ADRENOSTERONE WHICH COMPRISES REACTING4-BROMO-3,11-DIKETO17-HYDROXY-20-ACYLOXY PREGNANE WITH A TERTIARY AMINETO REMOVE THE ELEMENTS OF HYDROGEN BROMIDE FROM THE MOLECULE TO FORM THECORRESPONDING $4,5-3,11-DIKETO-17-HYDROXY-20-ACYLOXY PREGNENE;HYDROLYZING THIS COMPOUND TO THE CORRESPONDING 17,20-DIHYDROXYDERIVATIVE; AND REACTING THE RESULTING $4,5-3,11-DIKETO-17,20-DIHYDROXYPREGNENE WITH APPROXIMATELY THREE MOLECULAR EQUIVALENTS OF AN OXIDIZINGAGENT TO PRODUCE ADRENOSTERONE.